The Wistar Institute, HIV Immunopathogenesis Laboratory, Philadelphia, Pennsylvania, USA University of Pennsylvania Perelman School of Medicine, Department of Microbiology, Philadelphia, Pennsylvania, USA.
The Wistar Institute, Center for Systems and Computational Biology, Philadelphia, Pennsylvania, USA.
J Virol. 2015 Jan;89(1):799-810. doi: 10.1128/JVI.02382-14. Epub 2014 Oct 29.
Although monocytes and macrophages are targets of HIV-1-mediated immunopathology, the impact of high viremia on activation-induced monocyte apoptosis relative to monocyte and macrophage activation changes remains undetermined. In this study, we determined constitutive and oxidative stress-induced monocyte apoptosis in uninfected and HIV(+) individuals across a spectrum of viral loads (n = 35; range, 2,243 to 1,355,998 HIV-1 RNA copies/ml) and CD4 counts (range, 26 to 801 cells/mm(3)). Both constitutive apoptosis and oxidative stress-induced apoptosis were positively associated with viral load and negatively associated with CD4, with an elevation in apoptosis occurring in patients with more than 40,000 (4.6 log) copies/ml. As expected, expression of Rb1 and interferon-stimulated genes (ISGs), plasma soluble CD163 (sCD163) concentration, and the proportion of CD14(++) CD16(+) intermediate monocytes were elevated in viremic patients compared to those in uninfected controls. Although CD14(++) CD16(+) frequencies, sCD14, sCD163, and most ISG expression were not directly associated with a change in apoptosis, sCD14 and ISG expression showed an association with increasing viral load. Multivariable analysis of clinical values and monocyte gene expression identified changes in IFI27, IFITM2, Rb1, and Bcl2 expression as determinants of constitutive apoptosis (P = 3.77 × 10(-5); adjusted R(2) = 0.5983), while changes in viral load, IFITM2, Rb1, and Bax expression were determinants of oxidative stress-induced apoptosis (P = 5.59 × 10(-5); adjusted R(2) = 0.5996). Our data demonstrate differential activation states in monocytes between levels of viremia in association with differences in apoptosis that may contribute to greater monocyte turnover with high viremia.
This study characterized differential monocyte activation, apoptosis, and apoptosis-related gene expression in low- versus high-level viremic HIV-1 patients, suggesting a shift in apoptosis regulation that may be associated with disease state. Using single and multivariable analysis of monocyte activation parameters and gene expression, we supported the hypothesis that monocyte apoptosis in HIV disease is a reflection of viremia and activation state with contributions from gene expression changes within the ISG and Bcl2 gene families. Understanding monocyte apoptosis response may inform HIV immunopathogenesis, retention of infected macrophages, and monocyte turnover in low- or high-viral-load states.
本研究旨在描述低病毒载量与高病毒载量 HIV-1 患者单核细胞的激活、凋亡及凋亡相关基因表达的差异，提示凋亡调控的转变可能与疾病状态相关。
我们分析了 35 名（病毒载量范围：2243 至 1355998 HIV-1 RNA 拷贝/ml；CD4 计数范围：26 至 801 个细胞/mm(3)）未感染及 HIV(+)个体的固有及氧化应激诱导的单核细胞凋亡。固有凋亡和氧化应激诱导的凋亡均与病毒载量呈正相关，与 CD4 呈负相关，病毒载量超过 40000（4.6 log）拷贝/ml 的患者中，凋亡增加。与未感染者相比，高病毒载量患者的 Rb1 和干扰素刺激基因（ISG）表达、血浆可溶性 CD163（sCD163）浓度和 CD14(++)CD16(+)中间单核细胞的比例升高，这是意料之中的。尽管 CD14(++)CD16(+)频率、sCD14、sCD163 和大多数 ISG 表达与凋亡的变化没有直接关系，但 sCD14 和 ISG 表达与病毒载量的增加有关。对临床值和单核细胞基因表达的多变量分析表明，IFI27、IFITM2、Rb1 和 Bcl2 表达的变化是固有凋亡的决定因素（P = 3.77×10(-5)；调整后的 R(2) = 0.5983），而病毒载量、IFITM2、Rb1 和 Bax 表达的变化是氧化应激诱导凋亡的决定因素（P = 5.59×10(-5)；调整后的 R(2) = 0.5996）。
我们的数据表明，在与凋亡差异相关的不同病毒载量水平下，单核细胞存在不同的激活状态，这可能导致高病毒载量时单核细胞的更替增加。
本研究描述了低病毒载量与高病毒载量 HIV-1 患者单核细胞的激活、凋亡及凋亡相关基因表达的差异，提示凋亡调控的转变可能与疾病状态相关。使用单核细胞激活参数和基因表达的单变量和多变量分析，我们支持这样的假设，即 HIV 疾病中的单核细胞凋亡是病毒血症和激活状态的反映，其受到 ISG 和 Bcl2 基因家族中基因表达变化的影响。了解单核细胞凋亡反应可能有助于阐明 HIV 免疫发病机制、感染巨噬细胞的保留以及低病毒载量或高病毒载量状态下单核细胞的更替。
